Dr. Ray has the long term goal of pursuing independent investigation of the mechanisms operative in the pathophysiology of asthma. Receipt of a Clinical Investigator Award will facilitate the development of Dr- Ray's investigative skills and experience, by expanding his knowledge of several new pharmacologic and cellular physiologic techniques as outlined in the proposed studies. The learning objectives set out in this proposal, will foster Dr. Ray's progression to independent lines of investigation into the mechanisms of asthma. The specific aims in this proposal will extend earlier inquiries into respiratory heat and water transfers and the pathophysiology of hyperpnea-induced broncho- constriction, which Dr. Ray has begun under the guidance of Dr. Solway. Three immediate goals are defined: (1) Quantitate the local and distant airway responses to specific local mucosal drying/cooling stimuli in order to ascertain the pathway and mechanism of sensory nerve-effected responses in hyperpnea-induced bronchoconstriction (HIB). Tantalum bronchography and intravascular dyes will be used measure airway narrowing and bronchial hyperpermeability that results from neuropeptide release from sensory nerves during eucapnic dry gas hyperpnea in select animal models. These experiments will also test the hypothesis that the sensory nerve axon reflex leads to airway responses at sites distant from local thermal stimuli. (2) Define the mechanism by which the dry gas hyperpnea evokes tachykinin release. Specifically, fixed and circulating secretory cell interaction with sensory nerves during HIB will be investigated by measuring secretory cell mediators during dry gas hyperpnea in control guinea pigs or in animals manipulated through specific IgE sensitization or tachykinin depletion. (3) Identify the mechanisms that modulate tachykinin release and metabolism during dry gas hyperpnea and recovery. Using newly learned ELISA techniques, the time sequence of neuropeptide release during HIB, and factors which alter this sequence, will be identified. To test the clinical relevance of these results from animal studies, analogous experiments will be performed to examine the time course of bronchoconstriction in human adults with mild stable exercise-induced asthma. Potential changes in enzyme activity that may accompany mucosal drying/cooling which could affect neuropeptide actions will also be investigated. This work is particularly relevant given recent advances in research which have identified important actions of neuropeptides in a variety of airway responses. By clarifying the pathophysiology of neuropeptide containing sensory nerves in hyperpnea-induced bronchoconstriction and bronchovascular hyperpermeability in animals, the proposed work may provide insight into similar mechanisms in human asthma.